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(AIDSmeds.com) - Long-awaited data from a follow-up study of valproic acid (Depakote®) indicate that it is not likely to be a “cure” for HIV infection. The new report, published on the Journal of Infectious Diseases’ website ahead of its official printing, debunks a paper released two years ago suggesting that the widely available anti-seizure medication may help decrease the pool of “latent HIV” in the body and, in turn, potentially allow for the eradication of the virus. Back in 1995, papers published by researchers at the Aaron Diamond AIDS Research Center in New York and the University of Alabama suggested that HIV could possibly be eradicated from the body within three years of starting a protease inhibitor-based drug regimen. This theory was based on the assumption that all HIV-infected cells in the body are short lived and that combination antiretroviral therapy likely had the potency to snuff out viral replication completely.

In 1997, the publication of three additional papers threw a wet towel on the hope stemming from the 1995 findings. The papers – representing a series of studies conducted at Johns Hopkins University in Baltimore, the University of California, San Diego, and the National Institutes of Health in Bethesda – confirmed the presence of long-lived CD4 cell populations capable of harboring HIV for many months. Because these cells are “resting,” and because HIV medications can only go to work in HIV-infected cells that are actively dividing, the research teams estimated that eradication of the virus would require anywhere from 10 to 60 years of continuous “maximally suppressive” antiretroviral therapy.

Based on these and other observations, researchers have looked into ways to activate these long-lived resting cells so that standard antiretroviral therapy can get to the virus and stop it from replicating. Unfortunately, using immune-based therapies (such as Proleukin® [interleukin-2]) in combination with antiretroviral therapy did not work in this regard. A likely explanation for this is the fact that activation not only induced viral replication, it also increased the number of susceptible uninfected cells beyond the threshold that can be protected by antiretroviral therapy.

What was needed, it seemed, was a drug capable of inducing the expression of HIV hiding within these cells, while simultaneously limiting any activation of immune system cells. One such approach that has gained a lot of attention in recent years is the inhibition of histone deacetylase (HDAC), an enzyme believed to play a key role in maintaining HIV inside long-lived resting cells.

In 2001, it was determined that valproic acid – a medication commonly used to manage seizures, migraines, and bipolar disorder – is an inhibitor of HDAC, a finding that has resulted in great interest among researchers on the HIV eradication trail.

This was followed by another paper in 2005, authored by David Margolis, MD, of the University of North Carolina, Chapel Hill, and his colleagues, reporting on study results involving four HIV-positive patients receiving three months of valproic acid in combination with their antiretroviral drug regimens. In short, the study found that levels of HIV inside the quiescent cell population decreased dramatically. While Dr. Margolis’ group remained cautious in its interpretation of the results, they were widely seen by others as a sign that eradication of the virus may be possible after all.

Two years later, a new paper published by Janet Siliciano, PhD, of Johns Hopkins University and her colleagues has, unfortunately, concluded that valproic acid may not be the panacea many hoped it would be. The study enrolled nine HIV-positive patients taking antiretroviral therapy, along with valproic acid for at least three months for the management of neurologic and psychiatric problems.

Using a well-established assay to evaluate the size of the HIV reservoir in resting CD4 cells, Dr. Siliciano’s group reported that “latently infected cells were readily detectable in all patients studied and did not in general decrease over time in a given patient. The estimated decay of the latent reservoir was extremely slow and was similar to that previously reported for patients receiving [antiretroviral therapy] alone.” In other words, valproic acid’s affect on this hard-to-reach HIV population was limited at best.

While Dr. Siliciano group looked for key discrepancies between its research and the 2005 data published by Dr. Margolis’ group, there was no obvious explanation for the different results.

“Regardless of whether [valproic acid] proves to be useful,” Dr. Siliciano’s group writes in its concluding remarks, “the size of the latent reservoir through studies of the kind reported by [Dr. Margolis’ group] are of great importance, because cure of HIV infection cannot be achieved without elimination of the latent reservoir in resting CD4 cells.”

An accompanying editorial, written by Robert Schooley, MD, of the University of California, San Diego, and John Mellors, MD, of the University of Pittsburgh, implies that data from Dr. Siliciano’s group should not be seen as a letdown, but rather an important stepping stone to other avenues of eradication research.

“These studies should not be seen as failures but rather as examples of hypothesis-driven clinical investigation that should lay the groundwork for future work focused on achieving a cure,” Drs. Schooley and Mellors write. “There are a multitude of tools to apply to this goal, including small interfering RNA, passive cellular immune augmentation, therapeutic vaccination, stem cell biology, cellular activation with combinations of more-selective ligands – as well as combinations of these approaches.”

It would be interesting to read the entire article, but I'm not interested enough to pay 15 bucks to do so. I'll wait for publication,then go to the library.

Reading the abstract, it seems they looked at individuals taking long term valproic acid therapy for epilepsy who also had suppressed viral loads from HAART. They then did the latent reservoir assay to see how they compared to results they have seen with people only on HAART. They saw no difference. The half-life of a resting T-cell has been determined to be 44 months. If those in the study took VA for less than that period, one would not expect to see much effect on the latent reservoir. If they took it for over a year, then it's a whole other matter.

David Margolis' original four patients took VPA in conjunction with Fuzeon (and background HAART). It just MAY have been the Fuzeon, and not the VPA that caused the reduction in the reservoir. Or it could have been the combination of the two, combined with background HAART. Or perhaps the dosage of VPA to control epilepsy (used by Siliciano's patients) is not adequate to have any effect on the reservoirs.

In any case, research marches on. It will be interesting to see the results of Margolis' current study using VA without Fuzeon.

It will also be interesting to see how the study I'm currently in turns out, which is studying the effect of Fuzeon (but not VA ) on the latent reservoir. I just got my one-year latent reservoir blood draw a couple of weeks ago. Maybe there will be a change, who knows? That's what research is all about.....to find out.

The use of histone deacetylase (HDAC) inhibitors has revealed an essential role for deacetylation in transcription of IFN-responsive genes. The HDAC1 protein associates with both signal transducer and activator of transcription (STAT) 1 and STAT2, and IFN-{alpha} stimulation induces deacetylation of histone H4. Inhibition of HDAC1 by small interfering RNA (siRNA) decreases IFN-{alpha} responsiveness whereas expression of HDAC1 augments the IFN-{alpha} response, demonstrating that HDAC1 modulates IFN-{alpha}-induced transcription. Importantly, the innate antiviral response is inhibited in the absence of deacetylase activity. The requirement for deacetylase is shared by IFN-{gamma} transcription response and may represent a general requirement for STAT-dependent gene expression.

The series of hydroxamic acid-based hybrid polar compounds inhibit HDACs activity at or below micromolar concentrations, both in vitro and in vivo. X-ray crystallographic analyses of a HDAC-like protein (HDLP), isolated from an anaerobic bacterium, showed that the catalytic site of the enzyme has a tubular pocket with a zinc-binding site at its base and two Asp-Histidine charge relay systems (6) . The hydroxamic moiety of TSA and that of SAHA were shown to bind to the zinc at the base of the tubular pocket, and the carbon ring of these compounds projects out of the pocket onto the surface of the protei

Department of Biology, Active Biotech Research AB, BACKGROUND: Histone deacetylase inhibitors (HDACIs) induce hyperacetylation of core histones modulating chromatin structure and affecting gene expression. These compounds are also able to induce growth arrest, cell differentiation, and apoptotic cell death of tumor cells in vitro as well as in vivo. Even though several genes modulated by HDAC inhibition have been identified, those genes clearly responsible for the biological effects of these drugs have remained elusive. We investigated the pharmacological effect of the HDACI and potential anti-cancer agent Trichostatin A (TSA) on primary T cells. METHODS: To ascertain the effect of TSA on resting and activated T cells we used a model system where an enriched cell population consisting of primary T-cells was stimulated in vitro with immobilized anti-CD3/anti-CD28 antibodies whilst exposed to pharmacological concentrations of Trichostatin A. RESULTS: We found that this drug causes a rapid decline in cytokine expression, accumulation of cells in the G1 phase of the cell cycle, and induces apoptotic cell death. The mitochondrial respiratory chain (MRC) plays a critical role in the apoptotic response to TSA, as dissipation of mitochondrial membrane potential and reactive oxygen species (ROS) scavengers block TSA-induced T-cell death. Treatment of T cells with TSA results in the altered expression of a subset of genes involved in T cell responses, as assessed by microarray gene expression profiling. We also observed up- as well as down-regulation of various costimulatory/adhesion molecules, such as CD28 and CD154, important for T-cell function. CONCLUSIONS: Taken together, our findings indicate that HDAC inhibitors have an immunomodulatory potential that may contribute to the potency and specificity of these antineoplastic compounds and might be useful in the treatment of autoimmune disorders.

why did valproic acid fail, and what mechanism can i discover to make this a potential treatment, perhaps it takes two or three meds to cause the hiv to come out of the resting state, perhaps the body is to smart for just one path, usually there are reduntant systems in all chemical bio pathways so if one gets blocked the body can use another, was doses high enough

what about the interaction of the inhibition of histone deacetylase with the VA

perhaps the inhibition of histone deacetylase does not bring out the virus because...these arethe questons that i am going to set about finding anwer in the ppeer reviewed science...

latently infected cells were readily detectable in all patients studied and did not in general decrease over time in a given patient. The estimated decay of the latent reservoir was extremely slow and was similar to that previously reported for patients receiving [antiretroviral therapy] alone. In other words, valproic acid’s affect on this hard-to-reach HIV population was limited at best.

but what about the oxford study that talks about math models of infected cells

what about the CD8 disfunctionwhat about micro environments around those resting cells

Previously, we found that Rb can actively repress transcription of cell cycle genes by binding and inactivating transcription factors at the promoter. Here, we demonstrate that Rb can also repress transcription of endogenous cell cycle genes containing E2F sites through recruitment of histone deacetylase, which deacetylates histones on the promoter, thereby promoting formation of nucleosomes that inhibit transcription. These two mechanisms of repression by Rb are selective—some promoters and transcription factors are blocked by this recruitment of histone deacetylase, whereas others are resistant to histone deacetylase activity and are repressed directly by inhibition of transcription factors.

ArticleRb Interacts with Histone Deacetylase to Repress Transcription

Robin X Luo,1 Antonio A Postigo,1 and Douglas C Dean1

1Departments of Medicine and Cell Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA

2H. Lee Moffitt Cancer Center and Research Institute, Department of Medical Microbiology and Immunology, University of South Florida, Tampa, Florida 33612, USA

3Department of Biochemistry and Molecular Biology, University of Manitoba, Winnipeg, Manitoba, R3E OW3, CanadaSummaryTranscriptional repression by Mad–Max heterodimers requires interaction of Mad with the corepressors mSin3A/B. Sin3p, the S. cerevisiae homolog of mSin3, functions in the same pathway as Rpd3p, a protein related to two recently identified mammalian histone deacetylases, HDAC1 and HDAC2. Here, we demonstrate that mSin3A and HDAC1/2 are associated in vivo. HDAC2 binding requires a conserved region of mSin3A capable of mediating transcriptional repression. In addition, Mad1 forms a complex with mSin3 and HDAC2 that contains histone deacetylase activity. Trichostatin A, an inhibitor of histone deacetylases, abolishes Mad repression. We propose that Mad–Max functions by recruiting the mSin3–HDAC corepressor complex that deacetylates nucleosomal histones, producing alterations in chromatin structure that block transcription.

Division of Basic Science Fred Hutchinson Cancer Research Center, Room A2-025 Seattle, Washington 98104, USAThe bHLH-ZIP protein Mad heterodimerizes with Max as a sequence-specific transcriptional repressor. Mad is rapidly induced upon differentiation, and the associated switch from Myc-Max to Mad-Max heterocomplexes seem to repress genes normally activated by Myc-Max. We have identified two related mammalian cDNAs that encode Mad-binding proteins. Both possess sequence homology with the yeast transcription repressor Sin3, including four conserved paired amphipathic helix (PAH) domains. mSin3A and mSin3B bind specifically to Mad and the related protein Mxi1. Mad-Max and mSin3 form ternary complexes in solution that specifically recognize the Mad-Max E box-binding site. Mad-mSin3 association requires PAH2 of mSin3A/mSin3B and the first 25 residues of Mad, which contains a putative amphipathic a-helical region. Point mutations in this region eliminate interaction with mSin3 proteins and block Mad transcriptional repression. We suggest that Mad-Max represses transcription by tethering mSin3 to DNA as corepressors and that a transcriptional repression mechanism is conserved from yeast to mammals.